Obesity is associated with major health costs for the United States and affects more than 120 million people, including an increasing number of children. The underlying cause for the development of overweight and obesity is unknown. Leptin is a fat-derived hormone that normally reduces body weight in humans and in rodents. This occurs via actions on the brain leading to inhibition of appetite and stimulation of energy expenditure. However, for unknown reasons leptin is ineffective to reduce body weight and fat mass in obese animals and humans. This proposal is aimed at increasing the understanding of this issue. Normal mice given a Western-style high fat diet develop progressive obesity and leptin resistance. A central goal of this grant is therefore to use this widely accepted mouse-model of human obesity to determine why these animals become obese and why they are resistant to leptin. We have developed a highly sensitive immunohistochemical (IHC) method to anatomically measure leptin action and we have already determined that a specific region (arcuate nucleus) of the hypothalamus, but not other brain regions, is selectively resistant to leptin in obese mice. We will in this application determine the mechanism(s) of leptin resistance in the hypothalamus. Our overall hypothesis is that defective leptin action in the arcuate nucleus plays a role in development of obesity in DIO mice. Results from these studies would greatly increase our understanding of development of leptin-resistant obesity, and may help to unravel key mechanisms involved in body-weight regulation and sensitivity to a high-fat-containing Western diet. Ultimately, findings from this proposal may help to identify novel anti-obesity drug-targets that can eventually lead to development of new treatments for obese humans.